Abuse of psychostimulants such as cocaine has become a medical and social ill in this country, making it necessary to identify the cellular and molecular mechanisms underlying the behavioral effects that result from chronic adminstration of these drugs. Re-exposure to cocaine following a period of successful detoxification is a major determinant of relapse to drug-seeking behavior. Relapse among human addicts can be modeled in rats and primates by a self-administration paradigm, which has proven invaluable in elucidating the neural determinants of relapse. A growing body of evidence indicates that reinstatement of cocaine-seeking behavior is mediated by the interplay of dopamine and glutamate within the mesocorticolimbic pathway. The proposed research will expand on these findings by examining dopamine and glutamate transmission in cocaine reinstatement. The following pharmacological manipulations will be tested in animals in which self-administration behavior was previously extinguished. First, priming microinjections of cocaine will be administered into the subregions of the mPFC in order to assess the relative contributions of each region to relapse behavior. Second, the role of accumbal and mPFC D1-like and D2-like receptors in relapse will be examined. Animals will receive a priming microinjection of D1-like or D2-like dopamine agonists into the mPFC. In order to further assess the role of specific dopamine receptors in cocaine relapse, selective dopamine antagonists will also be administered directly into the mPFC prior to a systemic priming injection of cocaine. Although cocaine does not directly influence the glutamate system, recent studies indicate that the mPFC-accumbal glutamatergic pathway plays a role in reinstatement. Thus, in the third aim, AMPA and NMDA antagonists will be administered intra-accumbally prior to a priming microinjection of cocaine in the mPFC. Collectively, these experiments will help explore the role of the mPFC in modulating cocaine reinstatement.